The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Proteins During Stress (Note: papers from our group are cited) PROJECT SUMMARY The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various pathophysiological settings, including development, cancer and neurological disorders. We recently reported the unexpected discovery of stress-induced long noncoding RNAs derived from stimuli-specific loci of the ribosomal intergenic spacer (Mol. Cell (2012) 45:147), an enigmatic region of the human genome assumed to be transcriptionally inactive. Induction of intergenic spacer RNA (IGSRNA) converts the nucleolus from a factory of ribosomes to the nucleolar detention center: a molecular prison that detains specific proteins in response to extracellular stressors (Nature Cell Biol. (2004) 6:642; J.Cell. Biol. (2005) 170:733; Mol. Biol. Cell. (2013) 24: 2943). IGSRNAs capture and immobilize proteins in the nucleolar detention center by interacting with the Nucleolar Detention Sequence (NoDS), a discrete peptide code that regulates protein mobility (Mol. Biol. Cell (2007) 19:3966). We will show preliminary data that the rDNA intergenic spacer produces an array of novel and complex IGSRNAs that confine within the nucleolus distinct groups of proteins, depending upon environment cues. This enables cells to tailor their biological response to various adverse conditions by temporarily arresting critical pathways including DNA replication, transcription, translation and protein degradation. Based on these aforementioned rationales, we propose the following hypothesis: IGSRNAs induce cellular acclimatization to environmental stressors by capturing and immobilizing distinct proteins in the nucleolar detention center. In the Specific Aims, we will: 1- decipher the ribosomal intergenic spacer as a hub of lncRNAs responsive to environmental cues; 2- uncover the stimuli-specific nucleolar detention centers; 3- explore the biological and biochemical consequences of stress-specific IGSRNA-induced nucleolar detention. The discovery of the IGSRNA-regulated nucleolar detention pathway opens a unique and remarkable window of opportunity to investigate a largely unexplored post-translational mechanism involved in the cellular stress response. Study of the IGSRNA-directed pathway will yield significant conceptual advances in our understanding of critical adaptive/resistance processes to stressors encounter by cells, such as the acidotic tumor microenvironment, hyperthermia, and exposure to anti-cancer drugs.